A new channel of research
|Researcher Heike Wulff at work finding new drug targets for epilepsy.|
Ion channels. Most medical school graduates remember, in the deep dark recesses of their minds, learning something about them. But beyond calcium channels and heart muscle contraction, what was it they did again?
This obscure status is about to change. These cell portals are now taking center stage for a whole host of physiological processes. So many medical conditions have recently been discovered to have faulty ion channels as their underlying problem that the term "channelopathy" has joined the medical lexicon.
Who would have thought those tiny conduits could be so important?
Two scientists who have suspected it for years are Heike Wulff and James Trimmer with the Department of Medical Pharmacology and Toxicology at the UC Davis School of Medicine. They conduct their research in new laboratories in the Genome and Biomedical Sciences Building, the new six-story facility next to the medical school on the Davis campus that houses cutting-edge research in genomics, bioinformatics, biomedical engineering, and pharmacology and toxicology.
"Jim and Heike, taking totally different tacks, are at the forefront of discovering clinical applications for ion channels," says Ann Bonham, professor, executive associate dean for Research and Education and former department chair. "As pharmaceutical targets, ion channels offer enormous potential for treating a huge range of diseases."
A specialized superhighway
For anyone a little rusty on ion channels, they sit like a doughnut in a cell's lipid membrane, which is like a layer of olive oil separating the watery environment around the cell from the watery interior. The ion channel is a complicated protein — lipophilic on the outside and hydrophilic on the inside — that enables it to remain in the membrane yet connect the two watery worlds.
“An ion channel creates a road of water," Wulff explains. "This road, however, isn't for Sunday drivers — a million ions can zip through in only a second. Ion channels are needed when you want something to happen fast, like to communicate between neurons or to coordinate a muscle contraction.
"When the ion channel is needed, it opens up, and the ions fly out," continues Wulff. "It's like fireworks."
One amazing feature of these channels is that despite moving ions through at breakneck speeds, they are selective about which ions pass, marvels Trimmer. An ion channel may allow potassium ions to pass through, but not sodium ions, which are smaller. This occurs because of the channel protein's complex structure and configuration, which may favor rapid bonding and release with only a specific ion.
Trimmer's work centers on how neurons communicate with one another. Most efforts in this area have focused on neurotransmitters, but ion channels are actually responsible for the electrical activity that streaks through entire regions of the brain at lightning speed.
Certain forms of epilepsy, the most obvious disease of disordered electrical activity, have been firmly implicated in recent years as channelopathies. Some types of epilepsy are caused by ion channels that have altered proteins due to gene mutations.
While some ion channels cause electrical excitement, potassium-selective ion channels seem to play a calming role. A potassium channel opening stabilizes the cell membrane and inhibits further firing by the neuron.
Trimmer works with a diverse group of very specific ion channels in brain neurons in the hopes of discovering their specific roles in brain function. His lab is also characterizing enzymes located near the channels that enhance opening and closing of ion channel gates.
In addition to understanding basic mechanisms of brain function and dysfunction, designing drugs that specifically target certain ion channels or the enzymes that control them is the ultimate goal of this kind of basic research, according to Trimmer.
"Jim has an amazing ability to think about subtle changes in ion recognition and how they may be applicable to disease states," says Bonham. "He is opening up entire new lines of research into ion channel regulation as potential new drug targets."
|Department of Medical Pharmacology and Toxicology|
|Office of Research|
A chemist by training, Wulff studies ion channels that lie in the membranes of T cells, a cell type that was only discovered to have ion channels in 1984 by George Chandy and Mike Cahalan at UC Irvine.
T cells have been implicated in autoimmune diseases, particularly in multiple sclerosis. Activated in the peripheral circulation, the T cells invade the central nervous system and stimulate other cells to destroy the myelin sheath of neurons.
Where do ion channels come in? Potassium channels regulate the activation of T cells, and potassium ion channel blockers can prevent T cells from getting activated.
Unlikely as it may seem, a Caribbean sea anemone may carry an important clue to finding a cure for this difficult-to-treat disease. The sea anemone has a toxin that is exactly the reverse shape of the potassium ion channel implicated in multiple sclerosis.
"It fits like a plug in a bottle," says Wulff. "Why a sea anemone has a toxin that blocks an ion channel in a mammalian T cell — I don't know."
An animal model of multiple sclerosis has allowed Wulff and her colleagues to study the effect of the sea anemone's ion channel blocker. Not only does the toxin prevent symptoms of multiple sclerosis from developing in rats, but it ameliorates signs of disease that are already apparent.
This toxin is now synthesized artificially and may become an important drug for treating multiple sclerosis. But Wulff is not ready to rest on the laurels of this critical breakthrough. She points out that the toxin is a peptide, so it is digested if taken orally. This limits its destiny and can only work as an injectable, short-acting drug.
Could Mother Nature have created a similar ion channel blocker elsewhere, she wondered. Wulff pored through scientific literature and anecdotal accounts of likely candidates, and came up with the common rue, an herb that has been used medicinally since the Middle Ages.
"This plant is a chemical library in itself," says Wulff. She systematically isolated and examined the structure of the herb's ethereal oils, flavinoids, alkaloids, coumarins and furocoumarins. After two years, she found a potassium channel blocker. "At that point," she says, "we knew we were in business."
The first chemical they worked with had some serious drawbacks. It had only low affinity to the specific T cell ion channel involved in multiple sclerosis and caused unwanted side effects. Undeterred, Wulff put her organic chemistry skills to use and manipulated the molecules to try to create a better fit.
The result? A promising candidate that she hopes will undergo clinical trials within a couple of years. Her laboratory is currently testing this new compound, called PAP-1, in animal models of type-1 diabetes and psoriasis with very promising results.
"Heike's techniques have given her a way to map the structure inside ion channels," Bonham points out. "This can be enormously useful for a rational approach to drug design for many ion channel diseases."